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Determination of urinary coenzyme Q10 by HPLC with electrochemical detection: Reference values for a paediatric population. - BioFactors (Oxford, England)
Kidney dysfunction is being increasingly associated with mitochondrial diseases and coenzyme Q10 (CoQ) deficiency. The assessment of CoQ status requires the biochemical determination of CoQ in biological fluids and different cell types, but no methods have been developed as yet for the analysis of CoQ in excretory systems. The aim of this study was to standardize a new procedure for urinary CoQ determination and to establish reference values for a paediatric population. Urinary CoQ was analyzed by HPLC with electrochemical detection. Reference values (nâ€‰=â€‰43) were stratified into two age groups (2-10 years: range 24-109 nmol CoQ/gram of pellet protein; 11-17 years: range 43-139 nmol CoQ/gram of pellet protein). In conclusion, urinary CoQ analysis is a noninvasive, reliable, and reproducible method to determine urinary tract CoQ status. Â© 2015 BioFactors, 41(6):424-430, 2015.Â© 2015 International Union of Biochemistry and Molecular Biology.
Brazilian Portuguese version of the CORE-OM: cross-cultural adaptation of an instrument to assess the efficacy and effectiveness of psychotherapy. - Trends in psychiatry and psychotherapy
The Clinical Outcome in Routine Evaluation - Outcome Measurement (CORE-OM) was developed in the 1990s, with the aim of assessing the efficacy and effectiveness of mental health treatments.To adapt the CORE-OM for use in the Brazilian population.The instrument was translated and adapted based on the international protocol developed by the CORE System Trust which contains seven steps: translation, semantic equivalence analysis, synthesis of the translated versions, pre-testing in the target population, data analysis and back translation.After semantic analysis, modifications were necessary in seven of the 34 original items. Changes were made to avoid repetition of words and the use of terms difficult to understand. Internal consistency analysis showed evidence of score stability in the CORE-OM adapted to Brazilian Portuguese.The instrument was successfully adapted to Brazilian Portuguese, and its semantic and conceptual properties were equivalent to those of the original instrument.
Benchmarking of Density Functionals for the Accurate Description of Thiol-Disulfide Exchange. - Journal of chemical theory and computation
A set of 92 density functionals was employed to accurately characterize thiol-disulfide exchange. The properties we have benchmarked throughout the study include the geometry of a 15 atoms model system, the potential energy surface, the activation barrier, and the energy of reaction for thiol-disulfide exchange. Reference energies were determined at the CCSD(T)/CBS//MP2/aug-cc-pVDZ level of theory, and reference geometries were calculated at the MP2/aug-cc-pVTZ level. M11-L, M06-2X, M06-HF, N12-SX, PBE1PBE, PBEh1PBE, and OHSE2PBE described better the geometry of the model system, with average deviations of 0.06 Ã… in bond lengths (0.06 Ã… in bond-breaking lengths) and 1.9Â° in bond angles. On the other hand, the potential energy surface and its gradient were more accurately described by the hybrid density functional BHandH, closely followed by mPW1N, mPW1K, and mPWB1K. The barrier height and energy of reaction were better reproduced by the BMK and M06-2X functionals (deviations of 0.17 and 0.07 kcalÂ·mol(-1), respectively) for a set of 10 Pople's basis sets. MN12-SX and M11-L showed very good results for the widely used 6-311++G(2d,2p) basis set, with deviations of 0.02 and 0.05 kcalÂ·mol(-1), respectively. We studied the effect of the split-valence, diffuse, and polarized functions in the activation barrier of thiol-disulfide exchange, for a set of 10 Pople's basis sets. While increasing the splitting and polarization may increase the activation barrier in approximately 1 kcalÂ·mol(-1), diffuse functions generally contribute to decreasing it no more than 0.10 kcalÂ·mol(-1). In general, 13 functionals provided energies within 1 kcalÂ·mol(-1) of the reference value. The BB1K density functional is one of the best density functionals to characterize thiol-disulfide exchange reactions; however, several density functionals with modified Perdew-Wang exchange and about 40% Hartree-Fock exchange, such as mPW1K, mPW1N, and mPWB1K, show a good performance, too.
Catalytic Mechanism of Retroviral Integrase for the Strand Transfer Reaction Explored by QM/MM Calculations. - Journal of chemical theory and computation
Integrase (IN) is one of the three fundamental enzymes for the HIV life cycle. It irreversibly inserts the viral DNA into the host DNA, infecting the host cells. Although there are 37 compounds currently used in the HIV-1 antiretroviral therapy, only three have IN as a target. Lack of structural and mechanistic information on IN greatly contributes to such a small number. Prototype Foamy Virus (PFV) IN has an enzymatic activity remarkably similar to HIV IN and is considered a model system to study the catalytic mechanism of HIV IN. Recently, the crystal structure of the PFV intasome became available, which allowed us to perform accurate high-level quantum mechanics/molecular mechanics (QM/MM) calculations to determine the strand transfer reaction mechanism followed by IN. We describe here, for the first time with atomic detail, the integration of a viral genome into the DNA of a host cell. We found that the strand transfer reaction mechanism has three distinct steps: deprotonation and activation of the nucleophile; SN2 transesterification involving a pentacoordinated transition state; and protonation of the leaving group. The chemical steps have a limiting potential activation energy of 14.8 kcal/mol at the MPWB1K/6-311++G(2d,2p) level of theory, which is consistent with the upper limit established experimentally (25.1 kcal/mol) associated with the product release. This work improves the mechanistic knowledge on the IN chemistry and provides accurate structures of all the intermediates and transition states, which can be used as templates for the discovery of new IN inhibitors.
Establishing the Catalytic Mechanism of Human Pancreatic Î±-Amylase with QM/MM Methods. - Journal of chemical theory and computation
In this work, we studied the catalytic mechanism of human pancreatic Î±-amylase (HPA). Our goal was to determine the catalytic mechanism of HPA with atomic detail using computational methods. We demonstrated that the HPA catalytic mechanism consists of two steps, the first of which (glycosylation step) involves breaking the glycosidic bond to culminate in the formation of a covalent intermediate. The second (deglycosylation step) consists of the addition of a water molecule to release the enzyme/substrate covalent intermediate, completing the hydrolysis of the sugar. The active site was very open to the solvent. Our mechanism basically differs from the previously proposed mechanism by having two water molecules instead of only one near the active site that participate in the mechanism. We also demonstrate the relevant role of the three catalytic amino acids, two aspartate residues and a glutamate (D197, E233, and D300), during catalysis. It was also shown that the rate limiting step was glycosylation, and its activation energy was in agreement with experimental values obtained for HPA. The experimental activation energy was 14.4 kcal mol(-1), and the activation energy obtained computationally was 15.1 kcal mol(-1).
Periplasmic Nitrate Reductase and Formate Dehydrogenase: Similar Molecular Architectures with Very Different Enzymatic Activities. - Accounts of chemical research
It is remarkable how nature has been able to construct enzymes that, despite sharing many similarities, have simple but key differences that tune them for completely different functions in living cells. Periplasmic nitrate reductase (Nap) and formate dehydrogenase (Fdh) from the DMSOr family are representative examples of this. Both enzymes share almost identical three-dimensional protein foldings and active sites, in terms of coordination number, geometry and nature of the ligands. The substrates of both enzymes (nitrate and formate) are polyatomic anions that also share similar charge and stereochemistry. In terms of the catalytic mechanism, both enzymes have a common activation mechanism (the sulfur-shift mechanism) that ensures a constant coordination number around the metal ion during the catalytic cycle. In spite of these similarities, they catalyze very different reactions: Nap abstracts an oxygen atom from nitrate releasing nitrite, whereas FdH catalyzes a hydrogen atom transfer from formate and releases carbon dioxide. In this Account, a critical analysis of structure, function, and catalytic mechanism of the molybdenum enzymes periplasmic nitrate reductase (Nap) and formate dehydrogenase (Fdh) is presented. We conclude that the main structural driving force that dictates the type of reaction, catalyzed by each enzyme, is a key difference on one active site residue that is located in the top region of the active sites of both enzymes. In both enzymes, the active site is centered on the metal ion of the cofactor (Mo in Nap and Mo or W in Fdh) that is coordinated by four sulfur atoms from two pyranopterin guanosine dinucleotide (PGD) molecules and by a sulfido. However, while in Nap there is a Cys directly coordinated to the Mo ion, in FdH there is a SeCys instead. In Fdh there is also an important His that interacts very closely with the SeCys, whereas in Nap the same position is occupied by a Met. The role of Cys in Nap and SeCys in FdH is similar in both enzymes; however, Met and His have different roles. His participates directly on catalysis, and it is therefore detrimental for the catalytic cycle of FdH. Met only participates in substrate binding. We concluded that this small but key difference dictates the type of reaction that is catalyzed by each enzyme. In addition, it allows explaining why formate can bind in the Nap active site in the same way as the natural substrate (nitrate), but the reaction becomes stalled afterward.
Leukotriene C4 increases the susceptibility of adult mice to Shiga toxin-producing Escherichia coli infection. - International journal of medical microbiology : IJMM
Shiga toxin-producing Escherichia coli (STEC) is a food-borne pathogen that causes hemorrhagic colitis. Under some circumstances, Shiga toxin (Stx) produced within the intestinal tract enters the bloodstream, leading to systemic complications that may cause the potentially fatal hemolytic-uremic syndrome (HUS). Despite STEC human infection is characterized by acute inflammation of the colonic mucosa, little is known regarding the role of proinflammatory mediators like cysteine leukotrienes (cysLTs) in this pathology. Thus, the aim of this work was to analyze whether leukotriene C4 (LTC4) influences STEC pathogenesis in mice. We report that exogenous LTC4 pretreatment severely affected the outcome of STEC gastrointestinal infection. LTC4-pretreated (LTC4+) and STEC-infected (STEC+) mice showed an increased intestinal damage by histological studies, and a decreased survival compared to LTC4-non-pretreated (LTC4-) and STEC+ mice. LTC4+/STEC+ mice that died after the infection displayed neutrophilia and high urea levels, indicating that the cause of death was related to Stx2-toxicity. Despite the differences observed in the survival between LTC4+ and LTC4- mice after STEC infection, both groups showed the same survival after Stx2-intravenous inoculation. In addition, LTC4 pretreatment increased the permeability of mucosal intestinal barrier, as assessed by FITC-dextran absorption experiments. Altogether these results suggest that LTC4 detrimental effect on STEC infection is related to the increased passage of pathogenic factors to the bloodstream. Finally, we showed that STEC infection per se increases the endogenous LTC4 levels in the gut, suggesting that this inflammatory mediator plays a role in the pathogenicity of STEC infection in mice, mainly by disrupting the mucosal epithelial barrier.Copyright Â© 2015 Elsevier GmbH. All rights reserved.
Burden and quality of life of mothers of children and adolescents with chronic illnesses: an integrative review. - Revista latino-americana de enfermagem
to identify and analyze the evidence available regarding evaluation of burden and quality of life of mothers who are caregivers for children and adolescents with chronic illnesses.an integrative review, undertaken in the electronic sources MEDLINE; Academic Search Premier; CINAHL; LILACS; SciELO and PubMed, between 2010 and 2014.among the 22 documents selected, there was a predominance of convenience samples and non-experimental transversal designs, at the levels IV and III2. The caregiver burden scales used were the Zarit Burden Interview and Montgomery-Borgatta Caregiver Burden Scale-Revised along with the following instruments for evaluating quality of life: The World Health Organization Quality of Life-BREF Scale; Self-report questionnaires; The Ulm Quality of Life Inventory for Parents of chronically ill children; Asthma Caregiver Quality of Life Questionnaire; and the Nottingham Health Profile. Quality-of-life appears to be influenced in a complex and interrelated way by the physical and mental health of the mothers who are caregivers, in accordance with their level of independence, social relationships, environment, and the extent to which they see themselves as burdened.the revealing of the results for the evaluation of burden and quality of life of mothers who are caregivers has implications for the planning and implementation of effective interventions, by the multidisciplinary team, if they are to relieve the burden.
Preoperative Staphylococcus aureus Screening/Decolonization Protocol Before Total Joint Arthroplasty-Results of a Small Prospective Randomized Trial. - The Journal of arthroplasty
To study the prevalence of Staphylococcus aureus carriage and the impact of preoperatively treating carriers in prosthetic joint infection (PJI), a prospective randomized trial was organized. From January 2010 to December 2012, 1028 of 1305 total joint arthroplasties performed were screened, and selected carriers underwent preoperative decolonization. We observed a 22.2% (228/1028) S aureus colonization rate and only 0.8% methicillin-resistant S aureus. Prosthetic joint infection rate was higher, albeit not significantly, in S aureus carriers than among noncarriers-3.9% (9/228) vs 2.0% (16/800). Treated and untreated carriers showed no significant differences-3.4% (3/89) vs 4.3% (6/139). Most of the 14 S aureus PJI occurred in noncarriers suggesting a lack of causal relation between nasal and PJI S aureus. No clear benefit in screening/decolonizing carriers before total joint arthroplasty could be demonstrated.Copyright Â© 2016 Elsevier Inc. All rights reserved.
Nitric oxide synthesis by nitrate reductase is regulated during development in Aspergillus. - Molecular microbiology
Nitric oxide (NO) is a signalling molecule involved in many biological processes in bacteria, plants and mammals. However, little is known about the role and biosynthesis of NO in fungi. Here we show that NO production is increased at the early stages of the transition from vegetative growth to development in Aspergillus nidulans. Full NO production requires a functional nitrate reductase (NR) gene (niaD) that is upregulated upon induction of conidiation, even under N-repressing conditions in the presence of ammonium. At this stage, NO homeostasis is achieved by balancing biosynthesis (NR) and catabolism (flavohaemoglobins). niaD and flavohaemoglobin fhbA are transiently upregulated upon induction of conidiation, and both regulators AreA and NirA are necessary for this transcriptional response. The second flavohaemoglobin gene fhbB shows a different expression profile being moderately expressed during the early stages of the transition phase from vegetative growth to conidiation, but it is strongly induced 24â€‰h later. NO levels influence the balance between conidiation and sexual reproduction because artificial strong elevation of NO levels reduced conidiation and induced the formation of cleistothecia. The nitrate-independent and nitrogen metabolite repression-insensitive transcriptional upregulation of niaD during conidiation suggests a novel role for NR in linking metabolism and development.Â© 2015 The Authors. Molecular Microbiology published by John Wiley & Sons Ltd.
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